Ets2 is one member of the Ets transcription factor family that is essential for mouse development because of a key role in trophoblast stem cells. Ets2 functions in the stromal to support mammary tumors and additionally functions in macrophages and endothelial cells. It is activated by growth factor signaling pathways and contributes to the regulation of Cdx2, a homeobox regulator of both trophoblast and intestinal development. Ets2 has been proposed to be responsible for a repressive role of increased copies of the mouse equivalent of human chromosome 21 on experimental intestinal tumors. Our preliminary results indicate that Ets2 deficiency results in preferential colonization of colonic crypts and an increased rate of crypt fusion. We propose to determine if Ets2 restricts intestinal stem cells and tumor stem cells by inactivating Ets2 genetically and over expressing Ets2 in mice. Loss of function experiments will be performed with conditional alleles of Ets2 and intestinal stem cell specific expression of Cre recombinase. Gain of function experiments will utilize conditional expression of a new transgene driven by the keratin 18 gene and Cre recombinase expressed in intestinal stem cells. These experiments will test the hypothesis that Ets2 decreases sensitivity to intestinal tumors by regulating normal and tumor intestinal stem cells. PUBLIC HEALTH RELEVANCE: If colorectal cancer is a stem cell driven disease, therapeutic strategies to instruct cancer stem cells to differentiate to a benign fate are possible. Understanding the regulation of intestinal stem cells is fundamentally important for evaluating the risk of colon cancer formation and for identifying new strategies for therapeutic intervention.